Action of anticonvulsants on central neurotransmitters

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The anticonvulsants in clinical use may be divided into eight major groups. These are:

1. The barbiturates, such as phenobarbitone and primidone.

2. The hydantoins, such as diphenylhydantoin (phenytoin) and ethytoin.

3. The dibenzazepines, such as carbamazepine.

4. The oxazolidinediones, such as trimethadione (troxidone).

5. The succinimides, such as ethosuximide.

6. The benzodiazepines, such as diazepam, clobazam and clonazepam.

7. The sulphonamides, such as acetazolamide and sulthiame.

8. The short chain fatty acids, such as sodium valproate.

The chemical structure of representative drugs from each of these groups is shown in Figure 12.4.

Of the various animal models of epilepsy that have been developed to screen compounds for their potential therapeutic activity, antagonism of maximal electroshock seizures is generally indicative of the drug being useful in the control of partial seizures; drugs such as diphenylhydantoin and carbamazepine are active in such tests. Conversely, antagonism of pentylenetetrazol seizures is usually associated with the effective control of absence (petit mal) seizures, the succinimides and oxazolidinediones being particularly effective in antagonizing such seizures. Drugs such as sodium valproate and the benzodiazepines have a broad spectrum of action and are effective against primary generalized seizures (including petit mal) as well as partial seizures (including temporal lobe epilepsy).

The actions of anticonvulsants at the cellular level are complex and include facilitation of inhibitory feedback mechanisms, membrane stabilization and changes in synaptic transmission to reduce excitatory transmission. Of these various possibilities, it is widely accepted that anticonvulsants enhance GABA-mediated inhibitory processes. Such a mechanism has been clearly demonstrated for the benzodiazepines, barbiturates, diphenylhydantoin and sodium valproate.

Enhanced GABAergic transmission

Electrophysiological studies show that benzodiazepines, barbiturates and sodium valproate facilitate GABAergic transmission in the animal brain. Further evidence comes from studies on the GABA-benzodiazepine receptor complex, the order of potency of a series of benzodiazepines to displace [3H] diazepam from its receptor site being clearly correlated with the antagonism of pentylenetetrazol seizures, but not with electroconvul-sive seizures. However, most classes of anticonvulsants appear to facilitate

Figure 12.4. Chemical structure of the principal anticonvulsant drugs.

Sodium valproate

Figure 12.4. Chemical structure of the principal anticonvulsant drugs.

GABAergic transmission via the picrotoxin-binding site on the GABA-benzodiazepine receptor complex (see p. 56).

The precise mechanism of action of valproate in facilitating GABA transmission is still uncertain. There is evidence that the drug can facilitate

GABA synthesis, probably by inhibiting GABA transaminase activity, but the dose of drug necessary to achieve this effect is very high and not relevant to the clinical situation. One possibility is that valproate desensitizes GABA autoreceptors and thereby facilitates the release of the transmitter.

A reduction in the activity of excitatory neurotransmitters as a possible mechanism of action is largely confined to experimental studies on the barbiturates and benzodiazepines. In vitro studies have shown that drugs such as phenobarbitone can reduce the release of glutamate and acetylcholine, probably by impairing the entry of calcium ions into presynaptic terminals.

Membrane and ionic effects

The hydantoins have been most widely studied for their effects on ion movements across neuronal membranes. In the brain, these drugs have been shown to decrease the rise in intracellular sodium that normally occurs following the passage of an action potential; a reduction in calcium flux across excitable membranes also occurs.

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus.

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